复方茵陈注射液处方中增溶剂的选择

目的:选择增溶效果好而不良反应少的药用辅料。方法:分别采用泊洛沙姆188、吐温80作为增溶剂制备复方茵陈注射液,检查药物微粒数量、栀子苷含量、药液pH值、溶血与凝聚等指标变化。结果:2种复方茵陈注射液的栀子苷含量、pH值、微粒数、溶血与凝聚指标均合格。结论:泊洛沙姆188与吐温80具有同等增溶效果,可选择泊洛沙姆作为新一代增溶辅料。     

泊洛沙姆407研究新进展

目的：介绍泊洛沙姆407在医药学领域的研究新进展,方法：通过查阅近年国内外文献,选取有代表性学术期刊中的有关报道进行综述,结果：泊洛沙姆407在作为药用辅料、基因治疗、抑制术后肠粘连等方面具有良好作用,临床使用小剂量不会导致高脂血症。结论：泊洛沙姆407是理想的药物控释辅料。     

泊洛沙姆为载体的疏水性药物新剂型研究进展

目的综述高分子聚合物辅料泊洛沙姆近年来在提高疏水性药物溶解吸收和生物利用度方面的最新应用进展。方法查阅近2～3年来国内外研究文献,总结以泊洛沙姆407及泊洛沙姆188为载体的的各种疏水性药物给药新剂型及其载药特性和优点。结果以两类泊洛沙姆制备的给药新剂型主要有原位凝胶、固体分散体、纳米乳、纳米粒和复合制剂等,具有给药方便、增加药物溶解吸收、提高药物生物利用度及缓释效果显著等优点。结论两类泊洛沙姆是疏水药物新剂型研究的理想载体之一,尤其在中药难溶性有效成分给药系统研究中应用前景广阔。     

新型药用辅料—泊洛沙姆407急性毒性初步研究

目的：了解泊洛沙姆407的急性毒性作用。方法：泊洛沙姆407凝胶昆明小鼠腹腔注射（ip），观察小鼠死亡率及血丙氨酸转移酶（ALT）、尿素氦（BUN）、总胆固醇（CH）及甘油三酯（TG）含量变化。结果：中、小剂量泊洛沙姆407小鼠ip对ALT、BUN无明显影响，但可致血脂一过性增高；小鼠ip25％泊洛沙姆407凝胶5．0g／kg，死亡率为50％。结论：泊洛沙姆407是一个毒性较低的药用辅料。     

泊洛沙姆407的基础和药剂学新进展

目的介绍泊洛沙姆407的基础和药剂学新进展.方法通过查阅近年来国内外的相关文献,选取有代表性的学术期刊进行综述.结果泊洛沙姆407安全性好,在缓、控释凝胶系统及栓剂等剂型中有广泛的应用.结论泊洛沙姆407是安全、理想的药用辅料.     

蒸发光散射检测法测定重组人IL-12注射液中泊洛沙姆188

目的 建立定量测定重组人IL-12注射液中泊洛沙姆188的HPLC分析方法。方法 采用Waters Alliance系统、蒸发光检测器、赛分Poly RP-100色谱柱,以0.1% TFA水溶液（A）-0.1% TFA乙腈溶液（B）作为流动相梯度洗脱：0～5 min,50% A→50% A;5～6 min,50% A→5% A;6～12 min,5% A→5% A;12～13 min,5% A→50% A;13～20 min,50% A→50% A。体积流量1.0 mL/min,柱温30℃测定重组人IL-12注射液中泊洛沙姆188。结果 HPLC法测定泊洛沙姆188的保留时间RSD（n=6）为0.19%,峰面积RSD（n=6）为1.7%。泊洛沙姆188在低（50%）、中（100%）、高（150%）个浓度的回收率分别为93.3%、93.1%、93.8%,平均回收率为93.4%。泊洛沙姆188在1.5～9 μg（r>0.99）与峰面积呈良好的线性关系。结论 建立了重组人IL-12注射液中泊洛沙姆188含量检测的高效液相色谱法,并对建立的分析方法进行专属性、准确度、精密度、检测限、定量限、线性、范围和耐用性的验证,测定了3批重组人IL-12注射液中的泊洛沙姆188的量。     

新型药用辅料—泊洛沙姆407兔肝内注射后的动态变化

目的 探讨泊洛沙姆407凝胶肝内注射的可行性,了解其肝内注射后的动态变化。方法 采用超声技术动态观察了兔肝内注射泊洛沙姆407后的变化。结果 兔肝内注射泊洛沙姆407凝胶后数小时才被血流冲尽,相比之下,普通水溶液注射后即刻随血流被冲走。结论 泊洛沙姆407作为抗癌药物肝癌内注射的缓释载体是可行的。     

诺氟沙星阴道用温度敏感原位凝胶的制备及体外释放度研究

摘 要 目的：制备诺氟沙星阴道用温度敏感原位凝胶,并考察其体外药物释放行为。方法: 以泊洛沙姆为基质,采用冷溶法制备诺氟沙星阴道用温度敏感原位凝胶,考察泊洛沙姆407与泊洛沙姆188的用量对胶凝相变温度的影响,采用星点设计 效应面法优化其处方,并考察其体外药物释放行为。结果: 在一定浓度范围内,随着泊洛沙姆407用量的增大胶凝化温度逐渐降低,随着泊洛沙姆188用量的增大胶凝化温度逐渐升高,通过优化得到诺氟沙星阴道用温度敏感原位凝胶的最佳处方为：泊洛沙姆407的浓度为20.6%（w/v）,泊洛沙姆188的浓度为5.7%（w/v）,在温度为36.5 ℃以上可发生胶凝。药物在温度敏感原位凝胶中呈持续缓慢释放,6 h药物的累积释放度为87.5%±5.4%。结论: 诺氟沙星阴道用温度敏感原位凝胶具有很好的温度敏感性,可以延缓药物释放,有望开发成为一种新型阴道给药制剂。     

气相色谱法检测泊洛沙姆188中环氧化物杂质

目的 利用气相色谱法建立泊洛沙姆188中环氧乙烷、环氧丙烷及1,4-二氧六环的含量检查方法。方法 以超纯水作为溶剂,采用顶空气相色谱法检测泊洛沙姆188中环氧乙烷、环氧丙烷及1,4-二氧六环含量。结果 该方法的系统适用性、专属性、线性、精密度和准确度均符合规定,9批泊洛沙姆样品中均未检出环氧乙烷,环氧丙烷及1,4-二氧六环。结论 该方法简便、准确、可靠,可用于泊洛沙姆188中环氧乙烷、环氧丙烷及1,4-二氧六环含量检测。     

利巴韦林鼻用温敏凝胶热力学和流变学性质研究

考察了不同浓度泊洛沙姆407、PEG6000和泊洛沙姆188及处方量利巴韦林对鼻用温敏凝胶的热力学[胶凝温度（T1）、胶融温度（T2）]和流变学性质（黏度）的影响。结果表明，凝胶的T1和黏度均与泊洛沙姆407浓度呈负相关，而T2则与其呈正相关；利巴韦林和相应辅料对凝胶的T1、T2和黏度都有不同程度的影响。     

A Review of Poloxamer 407 Pharmaceutical and Pharmacological Characteristics

Abstract Poloxamer 407 copolymer (ethylene oxide and propylene oxide blocks) shows thermoreversible properties, which is of the utmost interest in optimising drug formulation (fluid state at room temperature facilitating administration and gel state above sol–gel transition temperature at body temperature promoting prolonged release of pharmacological agents). Pharmaceutical evaluation consists in determining the rheological behaviour (flow curve or oscillatory studies), sol–gel transition temperature, in vitro drug release using either synthetic or physiological membrane and (bio)adhesion characteristics. Poloxamer 407 formulations led to enhanced solubilisation of poorly water-soluble drugs and prolonged release profile for many galenic applications (e.g., oral, rectal, topical, ophthalmic, nasal and injectable preparations) but did not clearly show any relevant advantages when used alone. Combination with other excipients like Poloxamer 188 or mucoadhesive polymers promotes Poloxamer 407 action by optimising sol–gel transition temperature or increasing bioadhesive properties. Inclusion of liposomes or micro(nano)particles in Poloxamer 407 formulations offers interesting prospects, as well. Besides these promising data, Poloxamer 407 has been held responsible for lipidic profile alteration and possible renal toxicity, which compromises its development for parenteral applications. In addition, new findings have demonstrated immuno-modulation and cytotoxicity-promoting properties of Poloxamer 407 revealing significant pharmacological interest and, hence, human trials are in progress to specify these potential applications.     

Solution Stability of Poloxamer 188 Under Stress Conditions

Poloxamer 188 (P188) is a triblock copolymer of the form polyethylene oxide–polypropylene oxide–polyethylene oxide (PEO–PPO–PEO). The center PPO block is hydrophobic, and the side PEO blocks are hydrophilic, resulting in surface-active properties. P188 has been used in the pharmaceutical industry as an excipient in various formulations and drug delivery systems. Although the chemical stability of P188 in the solid state has been reported, there are very few reports detailing the solution state stability. In this study, we report the solution state stability of P188 conducted to evaluate the effects of P188 concentration, temperature, pH and buffer type, and trace metals on chemical stability. The degradation chemistry of P188 and identification of degradation products was studied using various analytical techniques (ultraviolet, gas chromatography–mass spectrometry, and liquid chromatography-mass spectrometry). The degradation of P188 in solution was found to be strongly dependent on temperature, P188 concentration, and buffer type. For the first time, we report that in histidine buffer, oxidation of both P188 and histidine may occur at pharmaceutically relevant conditions. We observed degradation of both histidine and P188 as well as species formed from the mutual interactions of the degradation products from the 2 types of molecules.     

Impact of Poloxamer 188 Material Attributes on Proteinaceous Visible Particle Formation in Liquid Monoclonal Antibody Formulations

Surfactants such as Poloxamer 188 (PX188) play an important role in controlling particle formation in biotherapeutic formulations due to interfacial stresses. This study demonstrates for the first time that hydrophobicity of PX188 is a potential critical material attribute (CMA) as far as control of visible particle (VP) formation is concerned. We have found that within PX188 lots satisfying pharmacopeial specifications, there is variability in material attributes such as hydrophobicity, as determined from their reversed-phase high-performance liquid chromatography profiles. However, it currently remains unknown how such variability in hydrophobicity of PX188 affects surfactant function and VP formation. Here, we compared the effect of seven PX188 lots in two monoclonal antibody drug product formulations under various stress conditions. Notably, proteinaceous VP formation was reduced while using a PX188 lot with higher hydrophobicity. Our findings emphasize the importance of monitoring lot-to-lot variability of PX188 and provide insight into potential CMA for improving and controlling material attributes of PX188 for use in liquid biotherapeutic formulations.     

苯甲酸利扎曲普坦原位凝胶鼻喷剂的制备

目的：一种新型治疗偏头痛的鼻喷剂——苯甲酸利扎曲普坦（RZTB）原位凝胶鼻喷剂的制备。方法：经大鼠的鼻腔灌流试验来筛选最佳浓度的吸收促进剂;通过测定胶凝温度确定原位凝胶材料泊洛沙姆407（P407）和泊洛沙姆188（P188）的合适比例;利用胶凝温度、黏度、粒径分布、喷射角度和每喷主药含量来调整处方中各组分的比例,确定RZTB原位凝胶鼻喷剂的最优处方。结果：羧甲基壳聚糖（CMCS）具有较好的吸收促进效果,制备的RZTB原位凝胶鼻喷剂的最佳处方为：20% P407、2% P188、0.1% CMCS和0.5% RZTB。结论：本实验所得的RZTB原位凝胶鼻喷剂,制备工艺简单可行,为曲坦类药物新剂型的研发提供了依据。     

Safety assessment of poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate as used in cosmetics

Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD(50) values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m(3) identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal toxicity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, or organ weight changes. A 6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day(-1)), Poloxamer 235 (tested up to 1.0 g/kg day(-1)), and Poloxamer 338 (at 0.2 or 1.0 g/kg day(-1)) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day(-1)) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day(-1) for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anticarcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multidrug-resistant cancer cells. In clinical testing, Poloxamer 188 increased the hydration of feces when used in combination with a bulk laxative treatment. Compared to controls, one study of angioplasty patients receiving Poloxamer 188 found a reduced myocardial infarct size and a reduced incidence of reinfarction, with no evidence of toxicity, but two other studies found no effect. Poloxamer 188 given to patients suffering from sickle cell disease had decreased pain and decreased hospitilization, compared to controls. Clinical tests of dermal irritation and sensitization were uniformly negative. The Cosmetic Ingredient Review (CIR) Expert Panel stressed that the cosmetic industry should continue to use the necessary purification procedures to keep the levels below established limits for ethylene oxide, propylene oxide, and 1,4-dioxane. The Panel did note the absence of reproductive and developmental toxicity data, but, based on molecular weight and solubility, there should be little skin penetration and any penetration of the skin should be slow. Also, the available data demonstrate that Poloxamers that are introduced into the body via routes other than dermal exposure have a rapid clearance from the body, suggesting that there would be no risk of reproductive and/or developmental toxicity. Overall, the available data do not suggest any concern about carcinogenesis. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used, and at what concentration, indicates a pattern of use. Based on these safety test data and the information that the manufacturing process can be controlled to limit unwanted impurities, the Panel concluded that these Poloxamers are safe as used.     

泊洛沙姆188-PLGA纳米给药系统对抗耐药肿瘤的研究

目的 利用泊洛沙姆188对PLGA进行化学修饰,制备包载阿霉素的纳米粒,并评价纳米粒在人耐药乳腺癌细胞中的摄取能力及毒性。方法 通过EDC/NHS法合成泊洛沙姆188-PLGA,通过核磁共振对其结构进行表征并测定临界胶束浓度;通过纳米沉淀法制备包载阿霉素的纳米粒,通过粒度仪对纳米粒的粒径及分布进行分析,通过细胞摄取实验及细胞毒性实验对纳米粒的摄取效果及毒性进行评价。结果 成功合成了泊洛沙姆188-PLGA,并制备了粒径在140 nm左右的纳米粒,该纳米粒在人耐药乳腺癌细胞中有较好的摄取效果及较强的毒性。结论 泊洛沙姆188能够逆转耐药,增强耐药细胞对化疗药物的敏感程度。     

Surfactant, but not the size of solid lipid nanoparticles (SLN) influences viability and cytokine production of macrophages

After intravenous (i.v.) injection, solid lipid nanoparticles (SLN) interact with mononuclear cells. Murine peritoneal macrophages were incubated with SLN formulations consisting of Dynasan 114 coated with different surfactants. The present study was performed to examine the impact of surfactants, which are important surface defining components of SLN, on viability and cytokine production by macrophages. Cytotoxicity, as assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) test, was strongly influenced by the surfactant used being marked with cetylpyridinium chloride- (CPC-) coated SLN at a concentration of 0.001% and further increased at SLN concentrations of 0.01 and 0.1%. All other SLN formulations -- containing Poloxamine 908 (P908), Poloxamer 407 (P407), Poloxamer 188 (P188), Solutol HS15 (HS15), Tween 80 (T80), Lipoid S75 (S75), sodium cholate (SC), or sodium dodecylsulfate (SDS) -- when used at the same concentrations reduced cell viability only slightly. None of the SLN formulations tested induced cytokine production but a concentration-dependent decrease of IL-6 production was observed, which appeared to be associated with cytotoxic effects. IL-12 and TNF-alpha were detected neither in supernatants of macrophages treated with SLN at any concentration nor in those of untreated cells. In contrast to the type of surfactant, the size of SLN was found neither to affect cytotoxicity of SLN nor to result in induction or digression of cytokine production by macrophages. In conclusion, testing the effects of surfactants on SLN on activity of macrophages is a prerequisite prior to in vivo use of SLN.     

Effect of Mechanical Properties on the Release of Meloxicam from Poloxamer Gel Bases

Thermoreversible gel of meloxicam, efficient for the treatment of joint diseases, was aimed to prepare for night application available for chronotherapy in this study. Poloxamer 407 and 188 polymers were used at 20-30% w/w as a vehicle in combination with different additives (polyvinylmethylether maleic anhydride copolymer, hydroxypropyl methylcellulose, polyethylene glycol 400, dimethyl sulfoxide, sodium chloride). Characterisation of prepared gels was evaluated by viscosity and texture analysis, and the effect of formulation variables on the gel formulations were evaluated by in vitro drug release and erosion studies. Between the investigated gel bases, Poloxamer 407-hydroxypropyl methylcellulose gel was found to be ideal due to its gel strength (1.560±0.0135 N), viscosity (312.3±2.06 cP) and release characteristics. These promising results could be encouraging for further studies to make it an alternative to commercial dosage forms.     

Preparation and in vitro/in vivo evaluation of mucosal adjuvant in situ forming gels with diphtheria toxoid

Abstract

Studies on preparation of in situ gel formulations containing diphtheria toxoid as the model active substance and their intranasal administration have been conducted in this study. The objective of mucosal vaccination is to stimulate both systemic and mucosal immune responses. In situ gel formulations were prepared by using, in different ratios, mixtures of Poloxamer 407 and Poloxamer 188 polymers, which gelate in a temperature-dependent manner, and mucoadhesive polymers carbopol 934, hydroxypropyl methyl cellulose, hydroxypropyl cellulose or chitosan. Following pre-formulation studies, F1, F2, F3, F4, F5, F6 and F7 formulations, which gelate at intervals and temperatures in accordance with nasal temperatures, were subjected to more comprehensive studies. For this purpose, organoleptic characteristics of the formulations were identified, their pH and mucoadhesive potencies were measured and rheological behaviors were characterized. Calculated amounts of diphtheria toxoid were added to formulations after optimization of formulations was achieved, and assay and in vitro release studies were carried out. Formulations coded F3 and F7 were considered to be superior to other formulations given the in vitro test results. Therefore, these formulations were tested in guinea pigs to determine immune responses, which they would produce following intranasal and subcutaneous administration. Absorbance values of ELISA tests and antibody neutralization test showed that formulations coded F3 and F7 were unable to stimulate adequate systemic immune response when either of the formulations was administered alone intranasally, whereas F7 resulted in significantly increased neutralizing antibody titers with intranasal administration as a booster dose following subcutaneous administration.     

In situ coating--an approach for particle modification and encapsulation of proteins during spray-drying

In this paper, we present a method for in situ coating of individual protein particles in a respirable size. The aim of the coating was to influence the particle/powder properties, and to reduce or prevent surface-induced conformational changes of the protein, during spray-drying, which was the method used for simultaneously preparing and coating particles. The investigated formulations included bovine serum albumin (BSA), trehalose and either of the two non-ionic polymers, hydroxypropyl methylcellulose (HPMC) and poly(ethylene oxide)-poly(propylene oxide) triblock co-polymer (Poloxamer 188). Complete protein coating as measured by electron spectroscopy for chemical analysis (ESCA) was achieved at a polymer concentration of approximately 1% of the total solids weight, and could be predicted from the dynamic surface tension at the air/water interface, as measured by the pendant drop method. Further, particle properties such as: size, dissolution time, powder flowability, and apparent particle density, as measured by gas pycnometry, were affected by the type and concentration of the polymer. In addition, the particle surface morphology could possibly be correlated to the surface elasticity of the droplet surface during drying. Moreover, an extensive investigation (Fourier transform infrared spectroscopy, circular dichroism and size exclusion chromatography) of the structural effects of protein encapsulated in a polymeric coating suggested that in situ coating provide particulate formulations with preserved native conformation and with a high stability during rehydration.